Pioneers of Promise
· · · · · · · · · · · ·
Before It Strikes
By Elaine F. Weiss
In the Chinese village of Qidong, near Shanghai, a large pictorial calendar has been hanging on the walls of several hundred homes. A glossy photo of the Johns Hopkins Hospital Dome, surrounded by Chinese characters, adorns its cover.
The calendar marks the progress of a yearlong clinical trial led by Hopkins School of Public Health scientists in the village. Color-coded squares remind participants which days to take their medication, when to come to the clinic for testing. The calendar also heralds the advance of a daring new approach to battling cancer. This strategy, called chemoprevention, aims to prevent cancers from forming by intervening in the way the body handles a carcinogen. By stimulating the body's own protective resources, researchers hope to thwart the carcinogenic process.
The same calendar hangs in the School of Public Health offices of Thomas Kensler and John Groopman and represents the culmination of more than two decades of their research. Groopman, the Anna M. Baetjer Professor and chairman of the Department of Environmental Health Sciences, and Kensler, a professor in the same department, have spent most of their professional lives studying the mechanics of how environmental toxins--specifically potent aflatoxins found in foods--can trigger cancer, and what might help the body protect itself from the carcinogenic exposure. In Qidong, where one of every 10 adults dies of liver cancer by the age of 45, Kensler and Groopman, together with SPH colleague Jai-Sheng Wang, have been testing the ability of the drug Oltipraz to block the carcinogenic effects of aflatoxins, which contaminate much of the village's grain supply.
Ever since the 1970s, when they were graduate students together at MIT, Kensler and Groopman have studied aflatoxins. These chemicals, produced by the fungus Aspergillus flavus, grow as a mold on many grains and nuts, including corn, peanuts, soy, and rice--some of the world's most important foodstuffs.
Aflatoxins are everywhere, even in U.S.-grown peanuts, corn, and grains, where stresses like draught or flood can make crops vulnerable. In the United States, the Food and Drug Administration closely monitors their levels, using a test developed by Groopman. Aflatoxins pose the most severe health risk in Asia and sub-Sahara Africa, where a hot, humid climate allows the mold to thrive in the field and in poorly ventilated storage facilities.
Aflatoxins are so potent that reportedly Saddam Hussein included them in his germ-warfare arsenal. They are a powerful hepto-carcinogen, causing cancer in the livers of animals and humans. Kensler and Groopman have spent years meticulously mapping the biochemistry and toxicology of aflatoxins in the body. When aflatoxin is ingested, it goes into the liver, where it is metabolized by multiple enzymes. These metabolic steps activate the aflatoxin to bond to, and damage, a molecule of DNA that controls the growth of liver cells, leading to mutation and carcinogensis.
In Qidong, which lies in the Yangtze River delta, aflatoxin-contaminated corn makes up more than half of the peasant diet; 95 percent of the thousands of villagers tested showed signs of exposure. Early in their studies in the village, the Public Health scientists found that the prevalence of chronic Hepatitis B infection among the residents of Qidong, combined with the ubiquitous aflatoxin exposure, multiplied the risk of developing liver cancer.
"We at least had a preventive strategy, a vaccine, for hepatitis B," says Groopman of the two-pronged public health challenge faced in that region of China. "The question was: Can we have a strategy for aflatoxin exposure?"
Enter Oltipraz, originally developed by Hopkins pathobiologist Ernest Buening as an antiparasitic drug to fight schistosomiasis. Studies had proven that Oltipraz was able to alter the metabolism of aflatoxin in the livers of rats, and completely protect them from developing liver cancer. Buening encouraged Kensler and Groopman to test Oltipraz's ability to boost protective enzymes in the human liver, altering the metabolic step in which aflatoxins become carcinogenic, and allowing aflatoxin to pass harmlessly out of the body. Using an analytic tool they'd developed for measuring aflatoxin-induced liver damage--the biomarker of aflatoxin bound to its target piece of DNA excreted in urine--the team, working with Chinese colleagues, conducted a short clinical trial of Oltipraz in Qidong in 1995. The results, published in early 1999, made big news: Analysis of the biomarkers showed that Oltipraz did inhibit aflatoxin from metabolizing into a carcinogen; the underlying mechanisms of the cancer process could be altered. The trial established "proof of principle" that Oltipraz could prevent liver cancer.
With the Phase IIb yearlong clinical trial just concluded, the optimum dosing regimens, longer-term benefits, and possible side effects of Oltipraz will be evaluated more thoroughly. "This is a hard road," explains Groopman, who is also associate director of cancer prevention and control at the JHMI Cancer Center. "Unlike chemotherapy--where you can develop an agent that demands tolerating some toxicity because you are trying to accomplish something very specific in the short term--with a preventive agent, you can't have any toxicity, because it will have to be taken for a lifetime.
"There is a rich history at this institution of chemopreventive research," says Groopman. "Paul Talalay has led the way--he's held biweekly meetings on chemoprevention topics here for the last 20 years," which have stimulated several other chemopreventive drug studies now under way at JHMI. Talalay is the J .J. Abel Distinguished Service Professor of Laboratory Molecular Pharmacology.
There is also a definite Hopkins slant to chemoprevention research, according to Groopman. "The philosophical concept we bring to bear at Hopkins is that the mechanistic science defines how you do the targeting. If you understand a disease process-- how you go from a normal cell to a diseased cell--there are pathways where you can intervene. The goal is to develop targeted places where you can block the process."
The potential of Oltipraz in inhibiting other types of cancers is the subject of a surge of clinical studies supported by the National Cancer Institute.
"All of these studies have been propelled to a higher plane by the clinical trial of tamoxifen," explains Groopman. Tamoxifen, which in a large clinical trial in the early 1990s indicated a 50 percent reduction of incidence of breast cancer in high-risk women, was the first drug to win FDA approval for chemopreventive use. The FDA approved a second drug recently for prevention of colon cancer in certain at-risk populations. "There's a growing body of evidence, in many of the major cancers, that the strategy to develop interventions can work," asserts Groopman.
"There's real excitement in the field," Kensler agrees. "We're seeing positive results in clinical trials now, and other successes are coming. The field is just now bearing the fruits of many people's labors."
Talalay, one of the most stalwart and influential laborers in that field, is in the midst of conducting trials of the chemopreventive potential of eating certain strains of broccoli sprouts, cultivated for high levels of sulforaphane.
"That's the real future in chemoprevention," says Kensler. "With our Oltipraz results, I think we've convinced a lot of people that drug intervention is going to be helpful in certain settings. A drug-based approach will work for those people most at risk, who will be highly motivated to stick with it over the long run. But for general prevention, over the course of a lifetime, the goal is to develop a simpler, gentler, cheaper, means of protection. We'll need a dietary approach."
If the future of the field lies in the garden, those seeds may still need a boost in the laboratory. "I think it's true that a number of chemical agents found in fruits and vegetables are capable of lowering your risk to a whole range of cancers," says Groopman. "To what extent can we enhance these agents--through genetic engineering, perhaps--to make it a practical form of prevention? If you must consume five pounds a day of a food with a protective agent, that's not practical. But if the agent can be engineered so that you just need 10 grams a day, that's more acceptable. But there's a lot of public resistance to the genetic engineering of plants now. That's going to be a very interesting debate, and one that's not likely to be settled very soon."
For now, Tom Kensler will make another trip to Qidong to bring home, in duffle bags, the last of the thousands of blood and urine specimens that need to be analyzed in his lab in East Baltimore. It will take another 18 months to finish the data analysis, and then there's the probability of another three- to five-year Phase III trial to determine if intervention with Oltipraz can actually prevent liver cancer.
But for the villagers of Qidong, where no family is untouched by liver cancer, and for many other villages around the world where aflatoxins bring disease, great hope hangs on the wall--in the color-coded days of that calendar with the Dome.
RETURN TO APRIL 2000 TABLE OF CONTENTS.